The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN)

Background This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. Methods Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. Results There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (− 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: − 51.1% and − 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: − 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was − 3.30 (p < 0.0001). Conclusions In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021 Supplementary Information The online version contains supplementary material available at 10.1186/s12931-023-02549-5.

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Patient's signed ICF obtained prior to any study-related procedure; 2.
Male or female ≥40 years of age; 3. Current smokers or ex-smokers of at least 10 pack-years, calculated as (number of cigarettes/day * number of years)/20 (e-cigarettes smoking could not be used to calculate pack-year history); 4.
Established diagnosis of COPD according to the 2020 GOLD Report, prior to the V1;

5.
Post-bronchodilator forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) <0.7 and FEV1 ≤60% of predicted at V1 (Note: if the criterion was not met at screening, the measure could be repeated once before run-in Day 1); 6.
On a stable dose of any non-extrafine ICS/LABA DPI twice daily regimen for at least 8 weeks before screening; 7.
Presence of lung hyperinflation based on the increase of TLC exceeding either the upper limit of normal (ULN) or 120% of predicted, and/or a plethysmographic FRC exceeding either ULN or 120% of predicted; 12.
Women of childbearing potential (WOCBP) fulfilling one of the following criteria: a.
WOCBP with fertile male partners: they and/or their partner had to be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up visit or b.WOCBP with non-fertile male partners (contraception was not required in this case).

13.
Female patients of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e., post-menopausal or permanently sterile; e.g., amenorrhea

Airway volume
The airways can be segmented up to the point where no distinction can be made between the intraluminal and alveolar air.This is where the airway diameter is around 1-2 mm, typically around the 7 th -10 th bifurcation, depending mainly on the disease state of the

Airway resistance
The iRaw is determined using computational fluid dynamics (CFD).During the CFD calculations, the outflow to each lobe is adjusted iteratively for each patient to match the internal flow rate distributions obtained from the segmentation of the CT scans.As a result, iRaw accounts for the patient-specific internal airflow distribution which might be greatly altered by the lung disease.Hence, the airflow distribution in the CFD calculations reflects Page 6 of 9 the airflow distribution as derived from the expansion of lung lobes from FRC to TLC.The iRaw is defined as the total pressure drop over an airway, divided by the flow rate through that airway.
The CT images at total lung capacity capture the first 7-10 generations.The airways beyond the 10 th generation cannot be directly visualised from the CT images but their characteristics can be inferred by including lobe expansion and hence the patient-specific internal airflow distribution in the CFD-based resistance calculation.
By segmenting the lobes at FRC and TLC for each patient, the patient-specific airflow distribution can be established by assessing lobar and volume expansion.The siRaw as an FRI parameter is derived from the iRaw.The specificity is calculated by multiplying the airway resistances with the lung resistances.This way, the airway resistances are normalised across patients and become specific, permitting comparison between patients.

Perfusion mapping
The volume of segmented pulmonary vessels are divided into three categories according to cross-sectional area, with BV5, BV5-10, and BV10 referring to vessels <5 mm 2 , 5-10 mm 2 , and >10 mm 2 in cross sectional area, respectively.These volumes are the combined volumes of the pulmonary arteries and veins, and because of variations in blood vessel volume based on overall body size, these measures are often expressed using the ratio to total blood volume (TBV).This way each of the measures expresses the fraction of blood vessel calibre present in each category.Lower values in small vasculature (<5 mm 2 ) may reflect CT imaging evidence of vascular pruning, i.e., a smaller proportion of the blood vessel volume comprised of small peripheral pulmonary blood vessels.The BVX data is the absolute value, expressed in mL.BVXPR data is expressed as % of all regional blood vessel volume.
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Lobar volume
Lobar volume (iVlobe) is an FRI-based ventilation parameter obtained by identifying and grouping voxels that represent the air in the lungs.

Air trapping
FRI-based air trapping is defined as all the intrapulmonary voxels with Hounsfield Units between -1024 and -850 using the expiratory scans at FRC.
COPD Assessment Test (CAT) score ≥10 at V1 and V2; 9. Documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months prior to V1; 10.Had a cooperative attitude and the ability to be trained and use correctly the DPIs; 11.Had a cooperative attitude and the ability to perform the required outcomes measurements (e.g., spirometry manoeuvres in sitting and supine position) and the ability to understand the risks involved; individual patient.From the resulting model, central and distal iVaw can be assessed at individual airways or in different regions.The distal airway volume is defined as the segmented airway volume starting from the 3 rd bifurcation.Visible airway generations can be different in the different visit scans.Trimmed airway volume indicates the volume of the generations of airways that are visible in the scans of all study visit days.The siVaw as an FRI parameter is derived from the iVaw.The specificity is calculated by dividing the airway volume with the lung volume.This way, the airway volumes are normalised across patients and become specific.Indeed, if two patients have the same airway volume, but have different lung volumes and thus different lung sizes, the patient with the larger lungs will have relatively smaller airway volumes.By dividing the airway volumes with the lung volumes, a comparison between lungs of varied sizes is possible.Also, if a treatment changes both lung and airway volumes (e.g., most treatments in COPD increase airway volumes whilst they decrease lung volume) the specific airway volumes often give an enhanced signal.

Table 1 .
Secondary multidetector computed tomography/functional respiratory imaging endpoints (per protocol set).Data are from 23 patients.BV5Pr, BV5-10Pr and BV10Pr, volume fraction of total pulmonary vascular volume contained in blood vessels with cross-sectional area <5 mm 2 , 5-10 mm 2 , and >10 mm 2 , respectively, with baseline values being the volume of blood vessels in each category; TLC, total lung capacity; FRC, functional residual capacity.Supplementary Table 2. Spirometry and body plethysmography (per protocol set).
Data are from 23 patients.